There are enormous species differences in the acute toxicity for TCDD and its structural analogs such as the polychlorinated dibenzofurans (PCDFs) . These compounds appear to exert their effects in in vivo and in vitro systems through a mechanism requiring the Ah receptor. TCDD is a potent hepatocarcinogen in female rats but not male rats. Our studies focused on potential mechanisms for the observed sex specificity by evaluating histological and biochemical parameters in a two-stage model for hepatocarcinogenesis in female rats using diethylnitrosamine (DEN) as the initiating agent and TCDD as the promoting agent. These studies revealed that ovarian hormones were required for the tumor promoting actions of TCDD in rat liver. In contrast, ovarian hormones prevented the tumor promoting actions of TCDD in lung. Dose-response relationships for TCDD effects on a number of parameters have been evaluated in rat liver within the framework of a tumor promotion model. These parameters include CYP 1A1 and 1A2 induction, epidermal growth factor receptor estrogen receptor, cell proliferation, preneoplastic lesions, clinical chemistries TCDD tissue concentrations, other dioxin responsive genes and possible oncogene activation. These studies have revealed that dose response relationships are different for different parameters. For example, CYP 1A1 and 1A2 induction occurs at much lower doses (0.1-0.3 ng/kg/day) than effects on cell proliferation or preneoplastic lesions. Other studies are comparing rodent and human responses by two approaches 1) in vitro culture of human and rodent lymphocytes with TCDD and 2) comparing rodin-t responses to human effects in cases where humans have been accidentally exposed to TCDD and/or its structural analogs. These studies indicate that human responses to TCDD are similar to those of rats.